A detailed comparison is
made of the metabolic response to starvation (up to several
weeks) between lean and obese subjects. Early starvation (1-3
days) is frequently associated with a transient increase in basal
metabolic rate (BMR) and protein oxidation. As starvation
progresses and lean body mass decreases, both BMR and protein
oxidation decrease. However, lean subjects, with their smaller
lean body mass than obese subjects, maintain a higher daily N
excretion in absolute terms, in relation to weight loss and in
relation to energy expenditure. Indeed, in lean individuals the
contribution of protein oxidation to BMR does not decrease as
starvation progresses (up to 45 weeks) but in obese individuals
it does, reaching values that are more than two-fold lower than
in lean subjects. The proportion of energy derived from protein
oxidation is inversely related to the body mass index (BMI) and
percent body fat. Such differences are considered to be of major
importance to survival, which can be several-fold longer in obese
individuals than lean individuals. In subjects ingesting
hypocaloric diets, the effect of initial adiposity on protein
oxidation and composition of weight loss is discussed in relation
to other confounding variables (e g., composition of diet,
duration of dieting, exercise, etc.). Recommendations are made
for nutritional support.

Although starvation and
hypocaloric dieting are often considered to produce a progressive
reduction in basal metabolic rate (BMR) and N loss, there is
little information as to the extent to which these changes depend
on initial body composition. This paper critically evaluates the
protein-energy interrelationships which occur during total
starvation and hypocaloric feeding, evaluates the physiological
significance of the differences that exist between lean and obese
subjects, and considers the implication for nutritional support
for those receiving very low calorie diets.

Although prolonged total
starvation is associated with an absolute reduction in basal
metabolic rate (BMR), during the first 2 days of starvation there
is often a small absolute increase in BMR relative to values
obtained after an overnight fast (Figure 1). Since this
change occurs while there is loss of body weight and lean tissue
(» 2%), the increment is greater when
expressed in relation to body weight or lean body mass. As early
as 1907, VAN NOORDEN wrote "during the first few days of
acute starvation the general metabolism of the body suffers no
diminution". However, a transient increase in metabolic rate
may have been missed, because the results were often compared to
measurement made at the end of the first day of starvation (36
hours since the last meal).

In other
studies it may have been missed because the first of a series of
measurements were made after a meal, as in the case of Cetti who
was first studied one hour after breakfast (LEHMANN et al., 1983).
The classic fast reported by BENEDICT in 1915 was associated with
a small increase in metabolic rate compared to values obtained
after an overnight fast (Figure 1), and so were a number
of other classic starvation studies in individual subjects. Four
of the five lean subjects studied by TAKAHIRA (1925) (not shown
in Figure 1) also showed an increase of up to 6% in
BMR during early starvation. The subject who did not show an
increase did not have a measurement made on day 2 of starvation.
More recent studies in groups of individuals have confirmed a
transient early increase in BMR (Figure 1). The rise in
BMR could be due to either an increase in the energy equivalent
of ATP gained as the body reduces the proportion of energy
derived from glycogen (73.3 kJ/mole ATP gained) increases and the
proportion derived from fat (79.2 kJ/mole ATP gained) decreases
(ELIA and LIVESEY, 1988; 1992), or an increase in the requirement
for ATP.

An
increased requirement may occur as a result of the increased
gluconeogenesis (ERIKSSON et al., 1988; FELIG et al., 1969),
increased triglyceride-fatty acid cycling (ELIA et al., 1987;
KLEIN et al., 1989), which is considered to account for
1-2% of the BMR during early starvation, increased protein-amino
cycling, which has been reported to increase during the first 3
days of starvation (NAIR et al., 1987), and increased
acetyl CoA-ketone body cycling. This last cycle occurs because
the liver synthesises ketone bodies from acetyl Coa (AcCoA),
while other tissues such as brain and muscle convert ketone
bodies back to AcCoA before final oxidation. This cycling (from
AcCoA to ketone bodies and back to AcCoA) has an energy cost of 1
ATP. Based on the rate of ketone body production and utilisation
during early starvation (ELIA, 1991) and the energy equivalent of
ATP (ELIA and LIVESEY, 1988; 1992), it is estimated that such
cycling could contribute to about 1-2% of the BMR during early
starvation.

Figure
1. Changes in resting energy expenditure during early starvation
expressed as a percentage of overnight fasted value (indicated as
100% at 12 hours)

In addition
to the early increase in energy expenditure, there is also some
loss of energy in the form of ketone bodies in both breath
(acetone) and urine (3-hydroxybutyrate and acetoacetate and
acetone). During early starvation in lean subjects this loss
corresponds to about 3 % BMR (ELIA et al., 1984a; REICHARD
et al., 1979). In obese subjects, the loss is less, but as
the circulating concentration of ketone bodies increases during
more prolonged starvation, the loss also increases (REICHARD
et al., 1979).

After the
first 2-3 days of starvation, the BMR becomes lower than after an
overnight fast. This reduction is partly due to loss of the
metabolically active lean tissues (during the first 3 days of
starvation there is a loss of about 30-35 g N; about 1.5-2% of
the total body N in a lean subject), and partly to changes in
metabolic rate per kg fat-free issue, by mechanisms which are
poorly understood.

Although the rate of
protein oxidation (reflected in the rate of urine N excretion) is
frequently considered to decrease during prolonged starvation,
especially in the obese (see below), several studies have shown
that there is often a transient early increase. Examples in lean
and obese subjects are shown in Figure 2, but similar
changes have been noted by a variety of workers (e.g., VAN
NOORDEN, 1907; BENEDICT, 1915; ELIA et al., 1984a;
TAKAHIRA, 1925). In the study of ELIA et al. (1984a), the
increase in N excretion could not be explained by loss of
preformed urea, because the circulating urea concentration showed
a tendency to increase rather than decrease (ELIA et al., 1984a).

It would
therefore appear that there is often genuine transient increase
in amino acid oxidation during early starvation. TAKAHIRA (1925)
suggested that this increased oxidation of protein was
responsible for the temporary increase in energy expenditure that
he observed in his starving subjects. This suggestion was based
on the premise that the specific dynamic action of catabolized
proteins is greater than that for fat or carbohydrate. It is also
of interest that the energy equivalent of ATP for protein is
greater than that of fat or carbohydrate (ELIA and LIVESEY, 1988;
1992).

Not all of
the N found in the urine during early starvation reflects protein
catabolism, since some of it is due to catabolism of free amino
acids, particularly glutamine. This amino acid has a greater
concentration in the circulation (»
0.5-0.7 mmol/L) and muscle (20-25 mmol/L intracellular water)
than any other alpha amino acid, and its release from muscle (as
well as that of several other amino acids), increases
significantly during early starvation (36-72 hours) (ELIA and
LUNN, 1989; POZEFSKY et al., 1976).

The pool of
free glutamine in muscle, estimated to be about 45 g or 15 g
glutamine nitrogen in a 70 kg man, almost halves between 12 and
72 hours of starvation (MAGNUSSON et al., 1987; ELWYN
et al., 1981). Since during this period there is a loss from
the body of about 28 g N (9-13 g N/d), the loss of free glutamine
from muscle corresponds to about 25% of the urine N excretion.
There is also a general tendency for other amino acids to be lost
from the free amino acid pool in muscle during short-term
starvation (MAGNUSSON et al., 1987) (although some amino
acids such as the branched-chain amino acids, which have only a
small pool size, may actually accumulate in muscle). However, the
absolute changes of these other amino acids are small, relative
to the loss of glutamine.

After the
first 2-3 days of starvation, urine N excretion begins to
decrease and generally continues to do so for most of the
subsequent period of starvation (although a premortal rise
frequently occurs).

The ratio of N excretion
(as an index of protein oxidation) to BMR is variable during
short-term starvation, but calculations based on the results of
several studies suggest a tendency for this ratio to transiently
increase during the first 2-3 days of starvation.

One of the most consistent
autopsy findings of animals and humans who died of 'pure'
starvation, is the virtual absence of depot fat, both
subcutaneously and internally (KEYS et al., 1950). In some
studies, fat was found to be replaced by a translucent gelatinous
material. In the autopsy of a man who refused all food until his
death, MEYERS (1917) confirmed the absence of storage fat from
most parts of the body, and noted that in those areas where small
amounts of fat persisted (e.g., pericardial fat), the boundaries
of the fat cells were maintained, but the cells which had become
small, were often completely filled with granular protoplasm
rather than fat. Therefore, individuals dying of starvation only
have a small amount of storage fat and a small amount of
structural fat, mainly in cell membranes and the brain and
nerves. Since body fat is the major store reserve of energy which
disappears during starvation, it is reasonable to suggest that
the initial amount of body fat is a major determinant of the
length of survival during starvation. Most of the weight loss
during starvation in lean individuals is due to loss of lean body
mass. A variety of autopsy studies in humans have shown that
25-50% of most lean tissues and organs are lost during
starvation. However, the brain, gonads and skeleton appear to be
preferentially preserved. Examples of the changes occurring in
humans and non-human species (cats, dogs and pigeons) during
'total' starvation are shown in Table 1.

Table 1.
Percentage loss of fresh organs during starvation

Pigeons

Cats

Rats

Dogs*

Man

Skeleton

3

10.4

14

5

-

Muscle

42

57.9

31

42

40.7

(Whole body)

Brain and cord

1

2.2

3

22

6.9

(Brain)

Heart

45

34.0

3

16

40.4

Spleen

71

68.5

-

57

18.4

Liver

53

59.8

54

50

28.6

Pancreas

64

55.1

-

62

48.8

Kidney

32

50.9

-

55

49.2

Lungs

32

20.5

-

29

28.6

Fat

-

-

97

-

-

* Loss of fresh
fat-free organs.

Based on
work by Chossat (pigeons), Sedlmair (cats), Voit (cats), Voit
(dogs) and Meyers (man) (summarized by MEYERS, 1917).

In the 19th
century and early part of the 20th century, various authors
believed in the concept of a lethal level of loss of body weight.
For example, KRIEGER (1921) suggested that the lethal level of
weight loss in adults was about 40% for acute starvation and 50%
for semi-starvation. This concept may have originated from
CHOSSAT (1843), who reported that animals dying of starvation had
lost 40-50% of their body weight. Death was considered inevitable
beyond these limits. However, even Krieger's own data
demonstrated substantial variation in the weight loss of subjects
dying of starvation. Other workers disagreed with the concept of
a critical lethal weight loss, and, as should become apparent
later in this paper, both the extent of weight loss and survival
time depend on the initial degree of adiposity (see Table 2 for
some remarkable world records of weight loss in fasting obese
subjects). Therefore, Krieger's figures can only be regarded as
an approximate guide.

The subject
studied by MEYERS (1917) who died 63 days after refusing food,
lost about 41% of his body weight. The mean weight of the
Northern Ireland festers at the time of death was 45 kg.
Unfortunately, it has proved difficult to establish their initial
body weight. However, if they had lost 40% of their body weight
their initial weight would have been 75 kg. In contrast, there
are several reports of successful total fasts in obese
individuals who have lost more than 50% of their body weight
(e.g., STEWART and FLEMING, 1973; COLLINSON, 1967; BARNARD et
al., 1969; FORBES, 1970; FORBES and DRENICK, 1979). If
starvation had continued until death, the weight loss could have
been substantially more.